4-1793594-C-A

Variant names:

• chr4-1793594-C-A
• rs4450996
• NM_000142.5:c.-103+129C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000142.5(FGFR3):​c.-103+129C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 149,608 control chromosomes in the GnomAD database, including 28,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28710 hom., cov: 30)
  • Exomes 𝑓: 0.72 (234 hom.)
• Consequence: FGFR3 NM_000142.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.95
• Publications: 5 publications found

Genes affected

FGFR3 (HGNC:3690): (fibroblast growth factor receptor 3) This gene encodes a member of the fibroblast growth factor receptor (FGFR) family, with its amino acid sequence being highly conserved between members and among divergent species. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds acidic and basic fibroblast growth hormone and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. [provided by RefSeq, Aug 2017]

FGFR3 Gene-Disease associations (from GenCC):

• achondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• camptodactyly-tall stature-scoliosis-hearing loss syndrome

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Crouzon syndrome-acanthosis nigricans syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypochondroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• lacrimoauriculodentodigital syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Muenke syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• thanatophoric dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• thanatophoric dysplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Genomics England PanelApp, Ambry Genetics
• thanatophoric dysplasia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• severe achondroplasia-developmental delay-acanthosis nigricans syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• isolated brachycephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated plagiocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000305534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-1793594-C-A is Benign according to our data. Variant chr4-1793594-C-A is described in ClinVar as Benign. ClinVar VariationId is 680176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000142.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	NM_000142.5	MANE Select	c.-103+129C>A		intron	N/A	NP_000133.1	P22607-1
	FGFR3	NM_001163213.2		c.-103+129C>A		intron	N/A	NP_001156685.1	P22607-2
	FGFR3	NM_001354809.2		c.-103+129C>A		intron	N/A	NP_001341738.1	X5D2G8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR3	ENST00000440486.8	TSL:5 MANE Select	c.-103+129C>A		intron	N/A	ENSP00000414914.2	P22607-1
	FGFR3	ENST00000481110.7	TSL:1	c.-103+129C>A		intron	N/A	ENSP00000420533.2	F8W9L4
	FGFR3	ENST00000260795.8	TSL:1	n.-103+129C>A		intron	N/A	ENSP00000260795.3	I6LM06

Frequencies

GnomAD3 genomes AF: 0.591 AC: 87844 AN: 148618 Hom.: 28701 Cov.: 30

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.562

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.597

GnomAD4 exome AF: 0.722 AC: 637 AN: 882 Hom.: 234 AF XY: 0.723 AC XY: 454 AN XY: 628

African (AFR) AF: 0.333 AC: 6 AN: 18

American (AMR) AF: 0.643 AC: 9 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 7 AN: 10

East Asian (EAS) AF: 0.885 AC: 23 AN: 26

South Asian (SAS) AF: 0.647 AC: 22 AN: 34

European-Finnish (FIN) AF: 0.722 AC: 13 AN: 18

Middle Eastern (MID) AF: 0.833 AC: 5 AN: 6

European-Non Finnish (NFE) AF: 0.743 AC: 535 AN: 720

Other (OTH) AF: 0.472 AC: 17 AN: 36

GnomAD4 genome AF: 0.591 AC: 87868 AN: 148726 Hom.: 28710 Cov.: 30 AF XY: 0.596 AC XY: 43257 AN XY: 72596

African (AFR) AF: 0.286 AC: 11665 AN: 40780

American (AMR) AF: 0.654 AC: 9861 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2014 AN: 3420

East Asian (EAS) AF: 0.882 AC: 4434 AN: 5028

South Asian (SAS) AF: 0.691 AC: 3312 AN: 4794

European-Finnish (FIN) AF: 0.744 AC: 7101 AN: 9544

Middle Eastern (MID) AF: 0.556 AC: 158 AN: 284

European-Non Finnish (NFE) AF: 0.709 AC: 47407 AN: 66832

Other (OTH) AF: 0.600 AC: 1242 AN: 2070

Alfa AF: 0.530 Hom.: 1699

Bravo AF: 0.571

Asia WGS AF: 0.728 AC: 2235 AN: 3072

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.86
PhyloP100		-1.9
PromoterAI		-0.15	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4450996; hg19: chr4-1795321;